Two types of drugs which block perception of pain without impairing consciousness have long been recognized. The narcotic analgesics are effective against both mild and severe pain and are thought to act on receptors located in the brain and spinal cord. The non-steroidal anti-inflammatory analgesics are effective against mild pain and act via inhibition of prostagland in synthetase. The objective of this proposal is to determine if there is a third class of drug action for pain attenuation: that of neuropeptides on peripheral sensory nerve endings (see pg. 10, diagram 1). We have spent the past two years characterizing the pharmacology of a system of peripheral opioid receptors located on visceral C fiber afferents in the cardiopulmonary tree of the rat. The receptors on these nerve endings may serve as a model for predicting actions of peptide analgesics on peripheral nerve endings. Specifically, we find that the sensitivity of these nerve endings are modified by endogenous factors (e.g. functional state of the adrenal and pituitary) and by exogenous agents such as dynorphin (1-13) and related analogs. In the coming years our major objectives would be to characterize. 1. The type of pharmacological effects produced by stimulation of peripheral opioid receptors. 2. The structural characteristics of opioid peptides that will activate these receptors and the selection of prototype agonists and antagonists for studying peripheral receptors, and 3. The conditions and variables, for example, endogenous or exogenous tolerance, by which the peripheral effects are modulated.